SECTION 2 Syndromes by Body System:

The Gastrointestinal System

KEY CONCEPTS were non-food-borne gastroenteritis (135 million cases per year) and
food-borne illness (76 million cases per year).3 A report from the US
• Diarrhea can be caused by a wide spectrum of viruses, bacteria Centers for Disease Control and Prevention (CDC) found that food-
and parasites. Multiple infections are common. borne diseases account for approximately 76 million illnesses, 325 000
• The spectrum of illness ranges from self-limited disease to a hospitalizations and 5000 deaths each year in the USA based upon
potentially deadly situation depending on the pathogen and surveillance data from multiple sources.4 In the Netherlands, the inci-
the host. dence of gastroenteritis was 45 per 100 person-years in a prospective
study.5
• In healthcare-associated diarrhea the cause is typically limited
Because some enteric pathogens such as Vibrio cholerae are not
to Clostridium difficile and norovirus.
ubiqui­tous, some pathogens are seasonal and some pathogens are
• Acute diarrhea can be diagnosed at the point-of-care by using responsible for epidemics, the prevalence of various pathogens respon-
rapid lateral flow and real-time polymerase chain reaction tests. sible for diarrhea is variable. The bacterial pathogens most frequently
• Recently available multiplex tests allow for a rapid syndromic found are enteropathogenic clones of E. coli, Shigella spp., Salmonella
diagnosis. enterica subsp., Campylobacter spp. and Aeromonas spp. The most
frequently identified causative viruses (outside local epidemics)
• Appropriate water networking, environmental surface cleans- include rotavirus, caliciviruses (norovirus and sapovirus), astrovirus
ing and hand hygiene are key to preventing outbreaks. and enteric adenovirus. Less prevalent viruses include paramyxovirus,
morbillivirus, rubivirus and reovirus. The prevalence of norovirus has
been recently estimated to be 12% in children under 5 years of age
Introduction hospitalized for severe diarrhea and 12% of mild and moderate diar-
rhea cases among patients of all ages.12 These authors estimated that
There is an increasingly recognized array of bacterial, parasitic and noroviruses were responsible for up to 200 000 deaths of children <5
viral organisms associated with infection of the intestinal tract which years of age in LMIC.12
can profoundly disrupt intestinal function with or without causing
acute diarrhea. Acute diarrhea is a syndrome that is frequently not SURVEILLANCE
differentiated clinically by a specific etiologic agent. The wide spectrum Not all enteric pathogens are notifiable, depending on the country.
of evolution varies from self-limited disease to death. Death is mainly Moreover, a recent study in six US states indicated that multiple steps
due to dehydration and acute diarrhea takes the highest toll among between onset of food-borne illness and its investigation by a public
children in low- and middle-income countries (LMIC). This chapter health agency could take up to 3 weeks.6
examines the viral and bacterial causes of acute diarrhea, clinically
defined by three or more loose or watery stools per day or a definite SOURCES OF PATHOGENS
decrease in consistency and increase in frequency based upon an indi- Infected persons, animals and the inanimate environment are sources
vidual baseline lasting for less than 2 weeks. Parasitic infections of the of pathogens. Indeed, diarrhea is a contagious situation where infected
gastrointestinal tract will be presented in Section 6 and diarrhea associ- persons are the main source of contamination, implying the isolation
ated with food poisoning is discussed in Chapter 37. Diarrhea associ- of the infected person as recalled by the recent outbreak of cholera in
ated with Clostridium difficile infection is covered in Chapter 40. When Haiti.7 However, some enteric pathogens are zoonotic and contami-
diarrhea lasts for 14 days it can be considered persistent; the term nated poorly cooked food is the source of infection, as in the case of
chronic generally refers to diarrhea that lasts for at least one month enteroinvasive Escherichia coli strains and Campylobacter8 and Listeria
(see Chapter 39). monocytogenes.9 Contaminated water is less likely to be a source of
infection except in circumstances where there is a leak between potable
Epidemiology and unpotable water networks. Water-borne outbreaks associated with
PREVALENCE recreational water (e.g., swimming or wading pools) are another
Acute diarrheal diseases ranked seventh in the causes of mortality in source of acute diarrhea. These are associated most frequently with
LMIC in the global disease burden series, 2013, with an estimated 1.3 Cryptosporidium (50%) in treated water sources and with toxigenic E.
million deaths (2.4 %).1 Most of these deaths occur in children under coli (25%) and norovirus (25%) in freshwater sources. When there is
the age of 5 years in LMIC and diarrhea remains among the top five a direct transmission of water-borne and food-borne pathogens, hands
causes of all deaths among children younger than age 5 years, as tabu- are increasingly recognized as vectors of enteric pathogens.10
lated in 2013.1 The incidence of acute diarrhea in the general popula- Travel is increasingly reported as a circumstance for acute diarrhea,
tion could be estimated by prospective studies such as those organized including enterotoxigenic Escherichia coli (ETEC) infection. Aeromo-
in the Food-borne Disease Active Surveillance Network (FoodNet) in nas infections have been traced to aquarium water.11
the USA. The network observed that 6% of interviewed people reported
an acute diarrheal illness during the 4 weeks preceding the interview, Pathogenesis and Pathology
that is an annualized rate of 0.72 episodes per person-year. Rates of Diarrhea reflects an increased water content of the stool, whether due
illness were highest among children younger than 5 years (1.1 episodes to impaired water absorption or active water secretion by the bowel.
per person-year) and were lowest in persons aged ≥65 years (0.32 In severe infectious diarrhea, the daily volume of stool may exceed 2
episodes per person-year).2 A study in 2000 that estimated the eco- liters. Dehydration and loss of potassium (hypokalemia) are two life-
nomic burden of both infectious and noninfectious gastrointestinal threatening consequences of severe diarrhea. Water is mainly absorbed
and liver disease in the USA found that the most prevalent diseases in the small bowel (about 8 liters a day in an adult) and further in the
335
336 SECTION 2 Syndromes by Body System: The Gastrointestinal System

colon. By the time the initial 8 liters of fluid reaches the ileocecal valve, blood cells. Although generally self-limiting, relapse with chronic diar-
only about 600 mL remain, representing an efficiency of water absorp- rhea is possible as well as extraintestinal infection including bacter­
tion of 93%. By the time the remaining 600 mL of fluid reaches the emia. C. jejuni infection is the most often recognized infection
anus, only about 100 mL of fluid remains, generally as formed feces. preceding the development of Guillain–Barré syndrome.15 The mecha-
In the small intestine, water is absorbed by three basic mechanisms: nisms rely on the cross-reactivity between ganglioside-like motifs
‘neutral’ sodium chloride (NaCl) absorption mediated by two coupled present in C. jejuni lipopolysaccharide and those of peripheral nerves.
systems – one of which exchanges Na/H (cation exchanger), and the Also, this species has been associated with immunoproliferative small
other exchanges Cl/HCO3 (anion exchanger); ‘electrogenic’ sodium intestinal disease.16 Species other than C. jejuni and C. coli are increas-
absorption where sodium enters the cell via an electrochemical gradi- ingly isolated from the stools of patients with diarrhea, including C.
ent – this electrogenic sodium absorption mechanism is commonly fetus, mainly isolated from extraintestinal sites, and C. upsaliensis. Both
damaged during acute enteric infection; and sodium co-transport species being susceptible to cephalothin, an antibiotic usually incor-
whereby sodium absorption is coupled to the absorption of organic porated in C. jejuni-selective media, their prevalence in stools and
solutes such as glucose, many amino acids and peptides. This diarrhea may be underestimated by culture methods.
co-transport mechanism remains intact during most acute diarrheal Clostridium difficile infection is discussed in detail in Chapter 40.
disorders. It is for this reason that oral rehydration is effective during
acute diarrheal illness. Escherichia coli Infection
Osmotic diarrhea occurs when an absorbable solute, such as lactose, E. coli organisms are common inhabitants of the intestinal tract of
is not absorbed properly and retains water in the gut lumen. Infections healthy people, yet a limited number of clones are responsible for acute
that damage the intestinal epithelial cells either directly (rotavirus) or diarrhea and extraintestinal infections. E. fergusonii is frequently iso-
by a toxin (Shigella spp.) cause malabsorption and osmotic diarrhea. lated from stools yet its pathogenic role is non proven, and E. albertii
Secretory diarrhea results from an active, toxin-mediated secretion of is a possible agent of acute diarrhea.17 There are five groups of E. coli
water into the gut lumen. This is observed during cholera, and infec- organisms associated with acute diarrhea: Shiga toxin-producing Esch-
tion by Shiga-toxin producing Escherichia coli and Shigella species. erichia coli (STEC), also named enterohemorrhagic Escherichia coli
Rotavirus also produces a viral enterotoxin, the nonstructural glyco- (EHEC); enterotoxigenic Escherichia coli (ETEC); enteropathogenic
protein (NSP4). Lastly, diarrhea can result from infection-mediated Escherichia coli (EPEC); enteroaggregative Escherichia coli (EAEC); and
intestinal inflammation. After ingestion, an enteric organism colonizes enteroinvasive Escherichia coli (EIEC). STEC produce one or several
the intestinal epithelium by adhering to enterocytes. One of two path- Shiga toxins also known as verocytotoxins and are the E. coli organisms
ways are generally followed depending upon the offending organism, most frequently associated with acute diarrhea in industrialized coun-
either mucosal invasion or production of an enterotoxin. tries. These organisms, including various E. coli O157 serotypes, are
responsible for mild non-bloody and bloody acute diarrhea.18 Non-
Clinical Features O157:H7 STEC are associated with illnesses that differ from those
caused by E. coli O157:H7. Most notably, they are found later and have
BACTERIAL ENTERITIS a lower proportion of bloody diarrhea than in patients infected with
Aeromonas Infection E. coli O157:H7.19 STEC are also responsible for an estimated 80% of
Aeromonas species are inhabitants of aquatic environments worldwide, HUS cases in about 4% of patients with enteric infection. Ground beef
including rivers and lakes as well as drinking water plants and distribu- has been the major vehicle of transmission of O157 STEC, although
tion systems. Also, most pathogenic Aeromonas species can be found other vehicles contaminated by bovine manure have been reported,
in meat and dairy products. Some Aeromonas isolates encode entero- including raw milk, sausage, apple cider, and raw vegetables and non-
toxins, including an alt gene-encoded heat-labile and an ast gene- chlorinated water supply. Also, person-to-person transmission is
encoded heat-stable enterotoxin. Aeromonas enteric infection may responsible for outbreaks in communities.
range from, most commonly, an acute watery diarrhea to dysenteric ETEC produce heat-labile (LT) and heat-stable (ST) enterotoxins
illness. Symptoms may include abdominal cramps (70%), nausea and are a frequent cause of acute diarrhea in LMIC, thus being a fre-
(40%), vomiting (40%) and fever (40%). Infection is usually self- quent cause of travelers’ diarrhea. ETEC infection manifests as rela-
limiting although children may rarely be hospitalized because of dehy- tively mild watery diarrhea and abdominal cramps, but without
dration. Aeromonas caviae is the most prevalent species. Aeromonas vomiting or fever. EPEC comprise organisms characterized by an
veronii can be associated with rare cholera-like illness and dysenteric adherence factor plasmid and the chromosomal locus of enterocyte
diarrhea resembling shigellosis with bloody and purulent stools. One- effacement. These organisms are responsible for severe infantile diar-
tenth of patients are coinfected with a second enteric pathogen. Inter- rhea in LMIC, associated with fever, vomiting and prolonged evolu-
mittent and persistent diarrhea may occur for years after initial tion. Chronic diarrhea may follow EPEC infection and be responsible
infection. Aeromonas enteritis can be complicated by the hemolytic for malabsorption, weight loss and growth retardation. EIEC are
uremic syndrome (HUS) and kidney disease.13 responsible for an infection mimicking shigellosis.
EAEC are responsible, worldwide, for mild enteric infections with
Campylobacter Infection non-bloody diarrhea, abdominal pain and mild fever.
Campylobacter species are motile, gram-negative, S-shaped, micro-
aerophilic organisms responsible for zoonoses. Not only food animals Salmonella Infection
such as poultry, cattle, sheep and pigs, but also domestic pets are res- The genus Salmonella comprises motile enteric bacteria of problematic
ervoirs for worldwide human infection. Although the incidence is nomenclature. Salmonella comprises two species and the species Sal-
decreasing in the USA, Campylobacter species are still responsible for monella enterica comprises five subspecies. The vast majority of human
sporadic infections following improper handling of poorly cooked infections are due to strains of Salmonella enterica subspecies I, also
meat. Poultry is a major source of infection.14 Unpasteurized dairy isolated from warm-blooded animals, while the other Salmonella
products and water have been found to be sources for limited out- organisms are isolated from the environment and cold-blooded
breaks. The incidence of infection with Campylobacter spp. is higher animals. These organisms are further serotyped and serotype generally
in LMIC than in industrialized nations and travelers to LMIC are at correlates with the food source of infection. Notably, Salmonella
risk of Campylobacter infection. The pathogenesis of Campylobacter enterica serotype Typhi is the agent of typhoid fever. Salmonella
infections is poorly understood. C. jejuni and C. coli are the most enterica serotypes Enteritidis and Typhimurium are the most com-
frequently encountered species responsible for diarrhea. Signs and monly isolated in LMIC.
symptoms may vary from asymptomatic infections to include fever, Non-typhoidal S. enterica organisms are responsible for acute diar-
abdominal cramps and diarrhea with or without blood and fecal white rhea with fever and abdominal cramps lasting for an average of one
 Chapter 38 Acute Diarrhea 337

week. Rarely, these organisms are responsible for bacteremia and on the basis of simple laboratory tests including the hemolysis of sheep
extraintestinal infections in immunocompromised patients. Contacts erythrocytes, the Voges–Proskauer test and resistance to polymyxin,
with animals and animal foods are the sources of infection with the which are all positive in the El Tor biotype. The first six historical
Enteritidis serotype, being associated with chicken and egg products. pandemics are thought to be due to the Classical biotype whereas the
Serotype Cholerasuis is adapted to cattle and serotype Dublin is on-going seventh pandemic since 1961 is due to the El Tor biotype.
adapted to pigs. The latter serotype harbors virulence traits in common V. cholerae O1 is the organism responsible for historical pandemics
with serotype Typhi, the typhoid fever agent. Typhoid fever is a life- of cholera since 1816, including the current pandemics. Most patients
threatening sepsis rarely observed in industrialized countries but still contaminated with V. cholerae O1 have an asymptomatic or self-
of public health concern in LMIC (see Chapter 115). Humans are the limited diarrhea (>75%), but massive contamination results in severe
only known reservoir for serotype Typhi, which is therefore transmit- diarrhea and large volumes of ‘rice water stools’ and dehydration.
ted by direct person-to-person contact and through contaminated Clinical manifestations include loss of skin elasticity, watery eyes,
water and food. A syndrome similar to typhoid fever is due to sero- painful muscle cramps and anuria. Dehydration leads to hypovolemic
types Paratyphi A, Paratyphi B and Paratyphi C. shock and death. Exceptional extraintestinal V. cholerae O1 bacteremia
infections have been reported.
Shigella Infection In 1992, cholera cases due to a new serogroup, V. cholerae O139
Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella son- (Bengal), were reported in India and Bangladesh and spread rapidly
nei20are responsible for acute diarrhea. Man is the only known reser- throughout Asia. The new serogroup probably resulted from the lateral
voir for Shigella spp. and transmission is by direct contact from gene transfer of novel capsule and somatic antigen genes to the El Tor
person-to-person and by contaminated water and food. Sexual trans- strains. It causes a disease similar to that caused by V. cholerae O1
mission has been observed in homosexual males. Most cases in indus- except that adults are more frequently infected.
trialized countries are imported from LMIC. Shigella spp. are Some V. cholerae isolates do not agglutinate with anti-O1 and anti-
responsible for bacillary dysentery characterized by acute, bloody diar- O139 antisera and are therefore referred as V. cholerae non-O1 isolates.
rhea accompanied by fever and abdominal cramps. Classic dysentery V. cholerae non-O1 isolates do not produce the cholera enterotoxin
is characterized by scant stools containing mucus, pus and blood. and are responsible for mild watery diarrhea. Unlike V. cholerae O1
Shigellosis is responsible for rectal and colonic ulcerations that do not isolates, V. cholerae non-O1 isolates are responsible for extraintestinal
develop beyond the lamina propria. Rare cases of sepsis have been infection such as life-threatening sepsis, especially in patients with
observed but Shigella spp. are responsible for HUS. previous liver disease or hematologic malignancies. V. cholerae non-O1
isolates have also been recovered from other anatomical sites.
Tropheryma whipplei Infection Other Vibrio species are responsible for diarrhea. They include V.
Tropheryma whipplei is an Actinobacterium and the etiologic agent of mimicus, a species phenotypically related to V. cholerae, which is
Whipple disease.21 Besides frequent fecal carriage in children,22,23 T. responsible for diarrhea after the consumption of raw seafoods; some
whipplei has been more recently recognized as an etiologic agent of strains harboring the cholera toxin can produce cholera-like symp-
mild gastroenteritis and diarrhea in children.24 Indeed, it was not toms. In Asia, V. parahaemolyticus is the leading cause of food-borne
detected in asymptomatic children but its DNA was detected with high intestinal infections after the consumption of raw fish or shellfish. The
bacterial loads in the stools of symptomatic children, followed by species is responsible for watery diarrhea, rarely bloody diarrhea and
disappearance in children recovering from diarrhea, associated with exceptionally is responsible for severe dehydration and death. A first
seropositivity.24 Adults also may present with T. whipplei diarrhea and pandemic clone of V. parahaemolyticus serotype O3:K6 emerged in
T. whipplei must be added to the list of agents responsible for travelers’ 1996 in Taiwan and then spread throughout Asia to America, Africa
diarrhea.25 In adults, however, there is asymptomatic fecal carriage of and Russia. New serotypes emerged for a few years. V. vulnificus is
the micro-organism26 and although the ultimate sources and precise primarily responsible for life-threatening sepsis and secondary skin
routes of infection are not elucidated, colonized persons are likely infection with necrosis; however, it has an intestinal route of entry and
sources of infection by the oro-oral and oro-fecal routes of transmis- is responsible for vomiting, diarrhea and abdominal cramps after the
sion. Diagnosis relies on home-made real-time polymerase chain reac- consumption of raw oysters. Three biogroups have been defined in V.
tion (PCR) assays tested on two different specific sequences.27,28 This vulnificus, the vast majority of infections being due to biogroup 1. V.
approach increases the sensitivity of diagnosis over 16S rRNA gene fluvialis, V. furnisii and Grimontia (Vibrio) hollisae cause sporadic cases
detection.29 There is no specific treatment for T. whipplei diarrhea. of diarrhea worldwide.32 V. alginolyticus is occasionally isolated from
stools but there is little evidence for V. alginolyticus being actually
Vibrio Infection responsible for intestinal infection and diarrhea.
Vibrio species are found ubiquitously in aquatic environments and
more than 70 Vibrio spp. are classified as responsible for trauma- Yersinia Infection
related, extraintestinal infections and intestinal infections with diar- Among the numerous members of the Yersinia genus, only Y. entero-
rhea.30 Vibrio cholerae is the etiologic agent of cholera. This is a motile, colitica and Y. pseudotuberculosis have been associated with digestive
gram-negative, facultative anaerobe bacterium which requires a small tract infection. Y. enterocolitica, further divided into two subspecies
concentration of sodium for growth. V. cholerae is primarily an aquatic enterocolitica and paleartica on the basis of 16S rDNA sequencing,33
inhabitant found in freshwater rivers and lakes as well as in estuarine comprises more than 70 serotypes, five of them being associated with
and maritime environments. In these environments, V. cholerae is human infection. These strains encode for an enterotoxin and some
isolated from both the inanimate environment and from plankton and strains harbor a chromosome-borne pathogenicity island which con-
various bivalves, crabs, shrimp and prawns. A viable-but-not-cultivable tains the yersiniabactin gene, providing the organisms with iron. Y.
state has been described in which regulation may be phage-dependent.31 enterocolitica is primarily an environmental organism isolated from the
V. cholerae comprises three major subgroups, V. cholerae O1, V. chol- gastrointestinal tract of numerous animals, most commonly swine,
erae O139 and V. cholerae non-O1, widely distributed in tropical and dogs and rodents. Its distribution is mostly in Northern Europe and
sub-tropical areas, including the Gulf of Mexico for V. cholerae O1. the northern USA, reflecting its increased growth at cold temperatures.
V. cholerae O1 chromosomes contain virulence cassette and pathoge- This species is responsible for gastroenteritis associated with the con-
nicity islands, encoding virulence factors such as the pilus responsible sumption of contaminated water and food, mainly poorly cooked
for the attachment of V. cholerae O1 organisms to the intestinal epi- swine meat. The disease spectrum comprises self-limited, acute diar-
thelium, and the cholera enterotoxin responsible for the substantial rhea to terminal ileitis and mesenteric lymphadenitis mimicking
excretion of electrolytes and water in the intestinal lumen. Two bio- appendicitis. Prolonged shedding has been observed. Sepsis is an
types, designated Classical and El Tor biotypes, can be differentiated uncommon complication observed in patients with an increased iron
338 SECTION 2 Syndromes by Body System: The Gastrointestinal System

pool, such as thalassemic patients in Western countries,34 liver disease, which resist in the inanimate environment comprising contaminated
cancer and receiving steroid therapy. Y. enterocolitica is a prominent surfaces, water and food. Outbreaks of norovirus infection are observed
cause of bacterial sepsis associated with blood transfusion. Reactive in daycare centers where child vomiting can readily contaminate floor
arthritis is an uncommon sequela observed in HLA-B27-positive and fomites.50 Accordingly, direct evidence for animals as reservoirs
patients and immunocompromised patients; it is characterized by an for human infection is still lacking. Noroviruses are the most prevalent
asymmetrical involvement of multiple joints, including the sacroiliac cause of nonbacterial acute enteritis worldwide.51 These viruses cause
joints and the spine. large outbreaks and provoke incapacitation for a few days; they have
Y. pseudotuberculosis is rarely isolated as a cause of a self-limited therefore been included in the list B of potential bioterrorism agents
acute diarrhea; it has been associated with outbreaks of gastroenteritis by the NIAID. Outbreaks mainly occur in institutions including
after consumption of contaminated fresh fruit and vegetables.35,36 healthcare centers. Cruise ships appear to be an emerging setting for
Y. pseudotuberculosis is also responsible for pseudoappendicitis, norovirus infection. Also, air flight has been shown to be a circum-
and reactive arthritis may develop after infection with Y. pseudotuber- stance for norovirus diarrhea, for both cabin crew and passengers.52
culosis O3.37 The inanimate environment in healthcare centers is also a source for
norovirus infection, and the viruses are resistant to routine cleansing
Miscellaneous Bacteria and routine alcohol hand hygiene.53
Arcobacter are Campylobacter-like organisms occasionally isolated The diagnosis can be made within 10 minutes at point-of-care
from the stools of patients with diarrhea, including Arcobacter but- thanks to commercially available immunochromatographic tests.
zleri38 and Arcobacter cryaerophilus DNA group 1B.39 Particular culture
conditions are required for proper isolation of these fastidious organ- Astrovirus Infections
isms, therefore limiting their detection to a few studies. Listeria mono- These RNA viruses, which average 30 nm diameter, are mainly respon-
cytogenes has only recently been recognized as an agent of acute sible for acute diarrhea in children, although outbreaks in military
enteritis, but it has now been associated with several outbreaks.40 troops and hospitals have also been reported. These worldwide viruses
Enteritis typically occurs after ingestion of a large inoculum and is are responsible for 2–10% of pediatric cases of acute diarrhea. Clinical
self-limiting after a few days.41 Klebsiella oxytoca is found in the envi- signs and symptoms are nonspecific.54
ronment but its principal reservoir is the human gastrointestinal tract.
K. oxytoca has been associated with C. difficile-negative antibiotic- Enteric Adenovirus Infections
associated colitis.42 K. oxytoca organisms cause experimental colitis and Adenoviruses look like non-enveloped, 100 nm round particles con-
exhibit cytotoxicity against HEp-2 cultured cells.42 Its culture is not taining DNA and are responsible for human infections. They belong
routinely performed and requires a specific isolation agar medium. to 51 different serotypes and six subgroups, but only two serotypes
Laribacter hongkongensis is a facultative anaerobic gram-negative bacil- Ad40 and Ad41 (subgroup F) have been clearly demonstrated to be
lus that was initially reported as being responsible for acute diarrhea agents of acute diarrhea. Clinical characteristics include a higher prev-
in Asian patients.43 Case–control study indicated that eating fish and alence in children <4 years of age and a mean duration of disease of
travel were associated with L. hongkongensis acute diarrhea.44 Dys- 5–10 days, that is longer than that caused by other viruses. Prolonged
gonomonas capnocytophagoides (formerly CDC group DF-3)45 are diarrhea has been observed in immunocompromised patients.55
Captocytophaga-like organisms isolated from the stools of immuno-
Miscellaneous Viruses
compromised patients.46–48
A few other viruses have been associated with acute diarrhea, yet their
VIRAL ENTERITIS role remains to be firmly established. These include coronavirus, a
definite agent of diarrhea in animals and seldom visualized by electron
Rotavirus Infections microscopy and isolated in culture from the stools of patients with
Rotaviruses are RNA viruses appearing as 70 nm particles with a diarrhea. Likewise, torovirus is responsible for acute human gastroen-
wheel-like appearance. Based on group-specific antigens of the major teritis and is responsible for nosocomial cases. Aichi virus, a picorna-
viral structural protein VP6, rotaviruses can be classified in six groups virus, has been characterized by reverse transcription-PCR during an
A to G. Groups A to C infect humans, the other groups are found in outbreak of enteritis following the consumption of oysters in Japan.56
animals. Human rotaviruses are responsible for severe acute diarrhea Picobirnaviruses have been detected in stools of animals and humans;
with dehydration associated with childhood death in low- and middle- their significance remains to be established. Recently, cardiovirus,
income countries. In Europe, children with rotavirus-positive acute closely related to Theiler’s murine encephalomyelitis virus, has been
gastroenteritis were more likely to have lethargy, fever, vomiting and detected in the stools in 1.2% patients with acute enteritis.57
dehydration, and, therefore, more severe disease than were children
with rotavirus-negative acute gastroenteritis. Dehydration was up to
5.5 times more likely in children with rotavirus-positive acute gastro-
Prevention
enteritis than in those with rotavirus-negative acute gastroenteritis.49 The global mortality from diarrhea declined from approximately 4.6
Acquisition of rotaviruses is likely from subclinical infection in parents million annual deaths during the mid-1980s, to 2.4 million deaths in
or siblings but rotavirus infection can be a zoonosis. Rotaviruses are 1990 and to the current estimate of 1.6–2.1 million.1 The decline is
resistant in the inanimate environment which may participate as a generally attributed to global improvements in sanitation and the use
source of infection, including nosocomial outbreaks. Rotavirus infec- of glucose-electrolyte oral rehydration therapy (ORT) which has dra-
tion is seasonal, with a peak of incidence in winter/spring in temperate matically reduced acute mortality from dehydration caused by diar-
countries. Clinical symptoms include acute diarrhea for 2–3 days, rhea. In contrast to the fortunate decrease of mortality, morbidity
fever, vomiting and anorexia. Rapid diagnosis at the point-of-care can remains as high as during the previous century. However, simple,
be achieved within 15 minutes by using a commercially available cheap measures could be undertaken to make the incidence fall.
lateral-flow assay with parallel detection of adenovirus. A prospective study in India demonstrated that the promotion of hand
washing with plain soap reduced by 53% the incidence of acute diar-
Calicivirus and Norovirus Infections rhea (and of pneumonia and impetigo).58 In industrialized countries,
The family Caliciviridae includes the genera Norovirus and Sapovirus, prevention relies on increased sanitary measures in sources of enteric
both responsible for enteritis. These RNA viruses appear as <40 nm pathogens such as recreational lakes for fishing and swimming, and
nonenveloped particles. Noroviruses comprise five genotypes, the swimming pools, as well as better control over fresh foods. A lifelong
genotypes I, II and IV are responsible for human infections, the two oral vaccine against rotavirus has been recently licensed after a few
other genogroups being animal-associated. Likewise, sapoviruses com- previous attempts and its safety and preventive effects have been care-
prise five genogroups, the genotypes I, II, IV and V are responsible for fully evaluated.59 Cost-effectiveness of a vaccine against rotavirus has
human infections. These human viruses are highly contagious viruses been evaluated favorably in the Netherlands.60
 Chapter 38 Acute Diarrhea 339

As for travelers, pre-travel prophylaxis relies on vaccines. There is Paratyphi C serotypes. O serotype determination is done by agglutina-
currently only one vaccine available that provides protection against tion using pooled antisera while further H serotype determination is
diarrhea caused by Vibrio cholerae and ETEC. This vaccine is licensed done by tube agglutination tests using broth culture and testing the
in only a few Western countries. Protective efficacy against cholera is two phases of the flagellar antigens. Campylobacter spp. are recovered
85%, while protection against the heat-labile toxin of ETEC reaches by using the filtration method in parallel to selective, blood-containing
67%. Current studies show a protective effect of up to 43%. Vaccina- or non-blood containing media and a micro-aerophilic atmosphere.
tion against cholera and ETEC should be recommended for at-risk Some Campylobacter spp. require 6% hydrogen in atmosphere. A 42 °C
travelers, in particular those with high exposure at their travel destina- incubation temperature allows the growth of C. jejuni and C. coli but
tion or high personal risks through fluid loss.61 Typhim Vi is a conju- not all Campylobacter and Aeromonas spp. are recovered using blood
gate vaccine aimed at prevention against typhoid fever; its safety and agar incorporating 20 µg/mL ampicillin and produce β-hemolytic
effectiveness have been favorably evaluated.62,63 During travel, system- colonies. Further identification should be done for oxidase-positive
atic administration of antibiotics including fluoroquinolones, cyclines and indole-positive colonies. Modified cefsulodin-irgasan-novobiocin
and trimethoprim–sulfamethoxazole (co-trimoxazole) is controver- agar is also suitable for the isolation of Aeromonas species. The inter-
sial. Prophylaxis may rely on the basic rules of boiling fresh water or pretation of recovery of Aeromonas in stools must be cautious since
drinking bottled water, and cooking foods. there is no strong evidence that all Aeromonas isolates from stools are
responsible for diarrheal infection.72
Blood cultures are mandatory for the diagnosis of typhoid fever as
Diagnosis well as bacteremia due to non-Typhi serotypes of Salmonella.
There is no recommended serologic test for the microbiologic diagno- The systematic search for other enteritis pathogens may depend on
sis of enteric pathogens, and the laboratory diagnosis of diarrhea relies local epidemiology, including Y. enterocolitica, Vibrio spp., K. oxytoca,
solely on direct diagnosis. Serologic testing is useful for epidemiologic L. monocytogenes and Plesiomonas shigelloides. Growth of Y. enteroco-
investigation of Campylobacter species infections.64 litica from stools is enhanced by incubation of selective media at 35 °C.
Fresh stools should be collected in a clean container with a tight A pectin agar should be used for the isolation of Y. enterocolitica from
lid. Alternatively, a transport medium incorporating buffered glycerol stools. V. cholerae will be visible as very motile, gram-negative slightly
in saline can be used. Rectal swab is an alternative specimen in selected curved bacilli cultivated using a TCBS agar after enrichment. Yellow
situations. It is well established that hospitalized patients who did not colonies of oxidase-negative bacilli can be confirmed, by 16S rDNA
enter the hospital with diarrhea are unlikely to develop diarrhea caused sequencing. In parallel to the search for pathogenic bacteria, the search
by other bacterial agents than C. difficile; therefore, stool culture for viruses should be done using electron microscope observation after
should not be performed in patients hospitalized for more than 72 negative staining as well as detection of rotavirus. Identification of
hours (the three-day rule) and a rapid detection of C. difficile toxins bacterial colonies is now routinely done by using matrix-assisted laser
should be performed.65 For routine purposes, testing a single stool desorption ionization time-of-flight mass spectrometry.73
specimen has acceptable sensitivity but testing a second specimen is
mandatory when the first one had a more than 2-hour delay in
transport.66 Management
Several techniques have been developed for the point-of-care diag- Management of acute diarrhea should include the clinical evaluation
nosis of diarrhea including the rapid (<30 minutes) agglutination- of the patient, including risk factors for specific etiology and dehydra-
based detection of rotavirus and adenovirus as well as the detection of tion; rapid diagnosis of viral diarrhea; and treatment, including rehy-
C. difficile toxins. The rapid detection of C. difficile toxins A and B dration, antibiotic treatment and symptomatic treatment. Rehydration
should be routinely performed for both out-clinic patients and hospi- is a major therapeutic measure. Oral rehydration has a higher risk of
talized patients. Point-of-care detection of Shiga toxin-producing paralytic ileus, but intravenous rehydration exposes patients to risks
Escherichia coli in children using EIA has not been evaluated favor- of intravenous therapy. For every 25 children treated with oral rehy-
ably.67 A commercially available Campylobacter antigen detection kit dration one will fail and require intravenous rehydration.74 Rapid diag-
has been favorably evaluated.68 A dipstick test for the rapid detection nosis of viral diarrhea is important in order to avoid unnecessary
of Shigella is under evaluation.69 antibiotic treatment. Because of the absence of any antiviral drug effec-
Multiplex real-time PCR assays are now commercially available for tive against the viruses responsible for acute diarrhea, the management
a 1–3-hour diagnosis of bacteria virus and parasites.70 of viral diarrhea comprises the relief of symptoms and rehydration.
Further detection of the causative organism relies on stool exami- Most acute diarrhea episodes are self-limiting and do not require anti-
nation in the clinical microbiology laboratory. Direct microscopic biotic treatment. Meta-analysis has confirmed that antibiotic treat-
examination may yield motile bacteria such as Vibrio and Salmonella ment is useful to shorten the duration of signs and symptoms in
species and parasites. Although Gram-staining analysis of stool speci- travelers’ acute diarrhea.75 When antibiotics should be prescribed,
mens may not be routinely done, it has demonstrated 66–94% sensitiv- fluoroquinolones are the drugs of first choice, and one-day treatment
ity and >95% specificity for the rapid detection of Campylobacter is advocated except for Campylobacter and Shigella infections, which
species.71 may be treated for three days.76 In the case of patients returned from
Culture of stools will focus on frequent pathogens and the system- countries where fluoroquinolone resistance is prevalent, such as Cam-
atic query of less frequent bacterial pathogens will be guided by the pylobacter spp. in Thailand, azithromycin (500 mg ×1/d) could be used
local epidemiologic situation. Pathogens routinely detected by culture for three days (see also Chapter 37 and Practice Point 11).77 Antimi-
of diarrheal stools include O157 E. coli, Shigella spp., S. enterica sero- crobial therapy for O157 E. coli enteritis remains a controversial issue
types, C. jejuni and C. coli and Aeromonas spp. Enrichment of stools because some studies reported a deleterious effect on the evolution of
in O157, O111 and O26 serotypes of E. coli can be done by using hemolytic uremic syndrome. The increasing resistance of S. enterica
specific, commercially available magnetic beads. Sorbitol MacConkey Typhi to antibiotics, notably to ciprofloxacin, makes the choice of
agar should be used for the isolation of O157 STEC as these organisms first-line antibiotic treatment of typhoid fever more problematic (see
do not ferment D-sorbitol, contrary to the vast majority of other E. Chapter 115). The majority of Y. enterocolitis gastroenteritis does not
coli strains. S. enterica serotypes are better isolated by using an enrich- require antibiotic treatment, contrary to systemic infection which
ment broth before plating onto selective media. Biochemical identifi- could be treated using trimethoprim–sulfamethoxazole (no resistant
cation of Salmonella spp. and O (somatic), H (flagellar) and Vi strain reported) or fluoroquinolones, despite the fact that a few resis-
(capsular) antigen serotyping should be performed in order to identify tant strains have been reported.78
Salmonella enteritis Typhi (the typhoid fever agent, being capsular
antigen Vi positive) and the most prevalent non-Typhi serotypes. The References available online at expertconsult.com.
Vi capsular antigen is occasionally detected in non-Typhi, Dublin and
340 SECTION 2 Syndromes by Body System: The Gastrointestinal System

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